Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH) is involved in many cellular functions, including cell growth and differentiation. GSH also plays an important role in the protection of cells against oxidative damage and hence in determining the sensitivity of cells to the cytotoxicity of anticancer agents. Because of this, induction of GSH depletion has been proposed as a good strategy for sensitizing tumor cells to antitumor agents. The aim of the present work is to study the effect of buthionine sulfoximine (BSO, a specific cellular GSH-depleting agent) in two rat tumor cell lines derived from the same rhabdomyosarcoma tumor model, the moderately differentiated and low metastatic F21 cell line, and the poorly differentiated and high metastatic S4MH cell line, to investigate the influence of the degree of differentiation in the induction of GSH depletion-based therapy. We observed that, whereas in the S4MH cell line BSO induced a dose-dependent inhibition of both cell growth in vitro and tumorigenic potential in vivo, in F21 cells the administration of moderate doses of BSO enhanced tumor growth and only at high doses was there a slight reduction of their tumorigenic potential. These effects were in consonance with the fact that the activity of gamma-glutamyltranspeptidase (gamma-GT) present in the F21 cells was 4 times higher than in the S4MH cells. Indeed, inhibition of gamma-GT activity by acivicin not only abrogated the BSO-induced increase of GSH content and of cell growth, but also the combination of acivicin + BSO significantly decreased intracellular GSH levels and cell proliferation, and induced F21 cells to apoptosis. These studies suggest that, as occurs in the rhabdomyosarcoma tumor model, gamma-GT levels and the degree of differentiation of tumor cells might influence the response of tumor cells to inducers of GSH depletion, and should be taken into account in therapies based on GSH metabolism.
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PMID:Role of gamma-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis. 1198 72

Differentiation therapy with retinoic acid has been considered a potential approach for treating rhabdomyosarcoma. Analysis of retinoids as differentiating agents for rhabdomyosarcoma is, however, rendered incomplete by the fact that some rhabdomyosarcoma cell lines are retinoic acid resistant. Therefore, the aim of the present work was to study the effect of all-trans-retinoic acid on two rat tumour cell lines, derived from the same rhabdomyosarcoma tumour model (i.e. the moderately differentiated low metastatic F21 cell line and the poorly differentiated high metastatic S4MH cell line), to discover how degree of differentiation and glutathione metabolism influence response to this retinoic acid derivative. We observed that whereas in the S4MH cell line all-trans-retinoic acid induced a significant inhibition of tumorigenic potential, in F21 cells all-trans-retinoic acid enhanced tumour growth and only at a higher dose was there a slight antiproliferative effect. These effects were in consonance with the activity level of gamma-glutamyltranspeptidase, which was significantly increased in F21 cells, but not in S4MH cells, in response to the all-trans-retinoic acid-induced increase in reactive oxygen species. The pro-tumour effect observed in F21 cells was reversed by adding buthionine sulphoximide, a specific cellular glutathione-depleting agent, to the all-trans-retinoic acid treatment. This combination produced a decrease in gamma-glutamyltranspeptidase activity, and an increase in oxidative stress and apoptosis. Our findings suggest that the response to all-trans-retinoic-acid of the tumour cell lines studied is influenced by the strong relationship between intracellular glutathione content, gamma-glutamyltranspeptidase activity and degree of differentiation of the rhabdomyosarcoma cell line, and that this relationship should be taken into account when identifying 'retinoid-sensitive' tumours.
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PMID:Influence of the level of gamma-glutamyltranspeptidase activity on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to all-trans-retinoic acid. 1707 12